It has long been known that histamine has a central role in the mediation of allergic reactions and it regulates gastric acid secretion. In the brain histamine regulates not only the basic homeostatic functions but higher brain functions as well such as learning and cognitive functions, sleep-wake cycle, food intake.
The histaminergic neurons originate from the tuberomamillary nucleus of the hypothalamus and send projections via the histaminergic path to most parts of the brain.
Histamine is an important biogenic amine involved in regulating physiological functions, the biological action of which is mediated via four receptors, named H1, H2, H3 and H4, their classification is based on their sequence differences, signaling properties and pharmacological profile (Haas and Panula, Nat Rev Neurosci (2003) 4:121-130; Leurs et al., Nat Rev Drug Discov (2005) 4:107-120; Esbenshade et al., Br J Pharmacol (2008) 154(6):1166-1181).
H1 and H2 receptors are known drug targets. The important role of H1 receptors in allergic responses is well known, H1 receptor antagonists are widely used. The main function of H2 receptors is regulation of gastric acid secretion. The role of H4 receptors has not been fully explored yet. According to preclinical evidences they can be involved in inflammatory processes and pain perception.
The histamine H3 receptor controls the histamine synthesis and release as an autoreceptor (Arrang et al., Nature (1983) 302:832-837), and as a heteroreceptor has an essential role in the regulation of the release of acetylcholine and other neurotransmitters (noradrenaline, serotonin, dopamine) (Schlicker et al., Naunyn Schmiedebergs Arch Pharmacol (1988) 337:588-590; Schlicker et al., J Neural Transm Gen Sect (1993) 93:1-10; Schlicker et al., Naunyn Schmiedebergs Arch Pharmacol (1989) 340:633-638; Clapham and Kilpatrick, Br J Pharmacol (1992) 107:919-923; Blandina et al., Br J Pharmacol (1996) 119:1656-1664).
Histamine H3 receptor antagonists/inverse agonists have a prominent role in the regulation of food intake and body-weight control via modulation of H3 receptors functioning as auto and heteroreceptors (Passani et al., J Pharmacol Exp Ther (2011) 336, 24-29).
Histamine H3 receptor antagonists evoke the synthesis and release of histamine and other monoamines in the brain. According to this mechanism they enhance wakefulness, improve cognitive functions, normalize vestibular reflexes. Histamine H3 receptor inverse agonists increase the synaptic release of histamine, which enhance wakefulness via activation of postsynaptic H1 receptors. The procognitive effect probably mediated not only via H3 autoreceptors, but other transmitter systems regulated via H3 heteroreceptors, such as cholinergic neurons, which play an important role in cognition, are also affected (Khateb et al., Neuroscience (1995) 69(2):495-506; Lin et al., J Neurosci (1996) 16(4):1523-1537; Passani et al., Trends Pharmacol Sci (2004) 25:618-625; Jones, Trends Pharmacol Sci (2005) 26:578-586; Bonaventure et al., Biochem Pharmacol (2007) 73:1084-1096; Ligneau et al., Biochem Pharmacol (2007) 73:1215-1224; Parmentier et al., Biochem Pharmacol (2007) 73:1157-1171; Haas et al., Physiol Rev (2008) 88:1183-1241).
Numerous H3 inverse agonists or antagonists have been described (Berlin et al., J Med Chem (2011) 54:26-53; Łazewska et al., Expert Opin. Ther. Patents (2010) 20:1147-1169; Raddatz et al., Cur Top Med Chem (2010) 10:153-169) since histamine H3 receptors were discovered (Arrang et al., Nature (1983) 302:832-837). Although several compounds have advanced to the clinical stage none of them gained therapeutic application, Phase 3 clinical trial has been started with only one compound, pitolisant (1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine), in narcolepsy indication (Kuhne et al., Expert Opin Investig (2011) 20:1629-1648). The main drawbacks of the histamine H3 receptor inverse agonist or antagonist compounds in getting a drug to the market were the following: (Łazewska et al., Expert Opin. Ther. Patents (2010) 20:1147-1169)                Phospholipidosis: there are one or two basic nitrogens in the structure of histamine H3 receptor inverse agonists or antagonists. Phospholipidosis is most probably caused by dibasic property, but in the case of monobasic compounds phospholipidosis can occur too (Ratcliffe Curr Med Chem (2009) 16:2816-2823). The dibasic JNJ-5207852 was rejected because it caused phospholipidosis (Bonaventure et al., Biochem Pharmacol (2007) 73:1084-1096).        Cardiovascular side-effects, interaction with the hERG potassium channel: ABT-239 (Hancock, Biochem Pharmacol (2006) 71:1103-1113)        High plasma protein binding: ABT-239 (Hancock, Biochem Pharmacol (2006) 71:1103-1113)        Genotoxicity: A-331440 (Hancock et al., Basic Clin Pharmacol Toxicol (2004) 95:144-152)        Poor pharmacokinetic characteristics: JNJ-5207852 (Bonaventure et al., Biochem Pharmacol (2007) 73:1084-1096). The spiro[benzopyrane-2,4′-piperidine]derivatives, which are structurally most closely related to compounds of our invention, but they have much less flexible structures, suffer from poor oral bioavailability therefore they should be further optimized. (Dandu et al., Bioorg Med Chem Lett (2012) 22:2151-2153)        CYP enzyme interaction: NNC 38-1202 (Peschke et al., Bioorg Med Chem (2004) 12:2603-2616)        
Elimination of the undesired properties from the potential histamine H3 receptor inverse agonists or antagonists is not an easy task considering that although several histamine H3 receptor inverse agonists or antagonists have undergone clinical investigation in different indications none of them was launched. (Kuhne et al., Expert Opin Investig (2011) 20:1629-1648)
The potential therapeutic application of histamine H3 inverse agonists and antagonists includes a variety of indications such as treatment options of neurodegenerative diseases and cognitive deficits.
There are two main types of medication used for symptomatic treatments of Alzheimer's disease, which belongs to neurodegenerative diseases, one of them is the use of acetylcholinesterase enzyme inhibitor drugs (such as donepezil, rivastigmine, galantamine, tacrine) while the other is the use of an NMDA receptor antagonist (memantine). Clinical trials showed that the combined administration of acetylcholinesterase inhibitors and memantine did not outperform the monotherapies. The efficacy of the so far approved drugs used in the monotherapy is limited, they have only weak effect in terms of improvement of cognitive functions and this effect is limited to the first 6-12 months of therapy, moreover acetylcholinesterase inhibitors are effective only in 30-40% of the treated patients. Common side effects are nausea, vomiting, loss of appetite and more frequent defecation.
Improvement of cognitive dysfunction caused by Alzheimer's disease represents an important unmet medical need; there is a high demand for new drugs (Gerald and Ockert, Nat Rev Drug Discov (2013) 12(1):19-20.; Molino et al., (2013) Scientific World Journal 2013: 925702; McGleenon et al., (1999) Br J Clin Pharmacol 48(4):471-480).
The efficacy of acetylcholinesterase inhibitors has been tried to be improved by co-administration with drugs having different mechanism of action.
In recent clinical trials the co-administration of histamine H3 inverse agonist or antagonist compounds with acetylcholinesterase inhibitors have been tried. In the case of three drug candidates there were no improvements on primary endpoints, therefore their further development was stopped (NCT01181310; Cho et al., Psychopharmacology (2011) 218(3):513-524; NCT 00420420; Egan et al., Curr Alzheimer Res (2012) 9(4):481-490; NCT01266525; Kirkesseli et al., J Nutr Health Aging (2013) 17(9):804).
The fact remains that there is no satisfactory monotherapy or combination therapy for the treatment of Alzheimer's disease.